Maternal stress prior to conception impairs memory and decreases right dorsal hippocampal volume and basilar spine density in the prefrontal cortex of adult male offspring
Introduction
Chronic stress has a substantial impact on the brain when experienced throughout life. Beginning in the 1960’s, Hans Selye characterized how chronic activation of the stress response can lead to the development of disease [1]. Over the past six decades, our understanding of how stress impacts brain and behavior has increased exponentially. Within the most recent decade, research has turned to examine how chronic stress prior to conception can impact subsequent generations [48,2,49,[3], [4], [5]]. This preconception (or pregestational, pre-reproductive) stress is of unique importance because it applies to both prospective parents; maternal and paternal preconception stress (MPS and PPS, respectively) both have large and varied impacts on the health and development of the subsequent offspring. Several studies have demonstrated the immediate consequences of preconception stress on early development [[6], [7], [8], [9], [10]], but here we focus on the long-term consequences for adolescent and adult offspring.
The initial experiments into MPS were conducted by Micah Leshem, Jay Schulkin, and colleagues one decade ago. First, they identified that maternal stress immediately prior to pregnancy impacts an array of behaviors in adolescent (post-natal day (P) 40-45) and adult (P60-65) offspring in a sex-dependent manner [11]. In a follow-up study, they showed that stress experienced by the prospective dam as a weanling also induces behavior- and sex-specific changes in future offspring [12]. This work demonstrated how adverse early experiences can impact the next generation, an effect that is also seen in human populations [13]. Others have found that MPS impairs adult offspring spatial learning and memory in the Morris water task [[14], [15], [16]], and results in depressive-like behaviors such as decreased sucrose preference [15,16], decreased novel environment exploration, and decreased latency to immobility in the forced swim task [16]. Increased anxiety-like behavior in the elevated plus maze, and impairment in a novel object recognition task [16] have also been reported. Conversely, in second generation offspring, variable MPS confers hypoactivity and potentially adaptive traits such as enhanced fear conditioning and exploratory behavior [17].
Accompanying the varied behavioral consequences of MPS in adult offspring, authors have reported changes in neuronal architecture in the prefrontal cortex (PFC; [18]), dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis [14,16,17,19], decreased brain-derived neurotrophic factor (BDNF; [14,16]), and perturbations to multiple neurotransmitter systems [16].
The present paper addresses if chronic consistent MPS has long-term implications for offspring brain and behavior. Previously, we demonstrated that this stressor impairs pre-weanling PFC development in the absence of changes to maternal care [8], and impairs offspring development throughout life when experienced by the sire [6,10,20]. Here, we expand on these findings by examining the long-term development of the same cohort from the Jenkins et al. [8] paper. Therefore, this is the first study to explore how consistent maternal stress prior to conception impacts adolescent and adult offspring. In our previous work, we showed that MPS alters cortical thickness of the PFC in the absence of changes in neuronal density in pre-weanling pups [8]. Here, we further examine how this stressor impacts PFC development in terms of structural plasticity. Additionally, the hippocampus and PFC share many connections and are both highly vulnerable to the negative effects of stress. Indeed, stress impairs physiological plasticity within the hippocampus-to-PFC pathway, which precedes a reduction in medial PFC volume and impairments in PFC-dependent behavioral tasks (working memory and behavioral flexibility; [21]). Therefore, we also examined structural plasticity within hippocampal subfields. In addition, we utilized a behavioral test battery to examine long-term behavioral development to explore if impairments are evident later in life despite apparently typical behavioral development in pre-weanling pups [8].
Behaviorally, we predicted that MPS would induce impairments in motor, cognitive, and emotional functioning in both adolescent and adult offspring. As described above, preconception stress exposure is commonly associated with impairments in cognitive and emotional behaviors. Although there is substantially less evidence associating stress with motor functioning, Harker et al. [20] found that PPS using the same stressor as the current work impaired fine motor control in both male and female offspring. Therefore, we sought to investigate if such an impairment is evident in the current experiment as well, thereby expanding the range of behavioral impairments due to MPS. In addition, we anticipated the effects to be sexually dimorphic as is typically observed following preconception stress exposure, as well as stress exposure more generally.
To assess the influence of MPS on structural plasticity, we estimated dendritic spine density in the PFC, parietal cortex, and hippocampus of adult offspring (P100). The PFC is critical for behavioral planning and control and emotional regulation, and is especially vulnerable to the negative effects of stress [[22], [23], [24], [25], [26], [27]]). We chose two areas in the PFC, the orbitofrontal region (agranular insular dorsal, AID) and the medial region (cingulate area 3, Cg3). Stress, including MPS, reduces dendritic spine density in the PFC, and especially in the medial PFC [18,28,25,26]); therefore, we predicted we would observe a decrease in PFC dendritic spine density in the adult offspring of MPS dams. We also measured spine density in the parietal cortex (Par1) to deduce if the effects of MPS on spine density are global or specific to regions commonly implicated in the response to chronic stress. To investigate the effect of MPS on the hippocampus, we estimated dendritic spine density in two hippocampal subfields (CA1 and CA3) as well as hippocampal volume. The hippocampus is implicated in two of the behaviors we assessed, learning/memory and anxiety-like behavior. The hippocampus is commonly divided into dorsal and ventral subregions that have that relatively distinct functions, with the dorsal hippocampus contributing to cognitive functions, such as spatial learning and memory, and the ventral hippocampus contributing to emotional behavior and regulation of the HPA axis [29]. Furthermore, both the dorsal and ventral hippocampi display functional lateralization, in which the left and right hemispheres are relatively specialized for distinct functions [30,31]. Therefore, we predicted that MPS would reduce the volume the dorsal hippocampus, associated with an impairment in spatial learning and memory, but increase the volume of the ventral hippocampus, associated with an increase in anxiety-like behavior [32], and that the changes in volume would be lateralized in accordance with any observed behavioral effects. We also predicted that MPS would impact basilar spine density in the dorsal (CA1) and ventral (CA3) hippocampus in a similar way.
Section snippets
Animals
All procedures were conducted in accordance with the Canadian Council of Animal Care and were approved by the University of Lethbridge Animal Welfare Committee. Sixteen primiparous female Long-Evans rats born in-house (eight maternal stress and eight control) were bred with 12 male Long-Evans rats. Both female and male animals were drawn from the internal breeding colony but were all behaviorally naïve. Ten pregnancies were successful (six maternal stress and four control), resulting in 80 MPS
Open field
Two-way mixed ANOVA with age as a within-subject factor and condition as a between-subject factor revealed no significant main effect of MPS on the total distance traveled in the open field for male, F(1, 8) = 1.379, p = .274, ηp2 = .147, or female offspring, F(1, 8) = 1.469, p = .260, ηp2 = .155. Likewise, there was no significant Age x Condition interaction for either sex, F(1, 8) = 1.244, p = .297, ηp2 = .135 and F(1, 8) = 0.399, p = .577, ηp2 = .041. There was a significant main effect of
Discussion
We demonstrate that a chronic, consistent stressor prior to conception has long-term consequences on the development of first-generation male offspring. We observed: 1) no effect of MPS on activity level or anxiety-like behavior in adolescent or adult offspring; 2) marginally, yet insignificantly, impaired fine motor control in adult male offspring following MPS; 3) impaired spatial memory in adult male offspring following MPS; 4) reduced basilar dendritic spine density in the medial PFC of
Author Contributions
S Jenkins (Experimentation, Analysis, Writing).
A Harker (Conception).
R Gibb (Conception, Editing, Supervision).
Funding
This work was supported by the Natural Sciences and Engineering Research Council to R.G. [grant number 312374-2006]; the Natural Sciences and Engineering Research Council CGS-M to S.J.; and Branch Out Neurological Foundation Master’s Grant to S.J.
CRediT authorship contribution statement
Serena Jenkins: Data curation, Formal analysis, Investigation, Writing - original draft. Allonna Harker: Conceptualization, Methodology. Robbin Gibb: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing - review and editing.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
The authors would like to acknowledge Animal Care Services at the University of Lethbridge for their essential role in animal husbandry.
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